Enol ethers as substrates for efficient Z- and enantioselective ring-opening/cross-metathesis reactions promoted by stereogenic-at-Mo complexes: utility in chemical synthesis and mechanistic attributes

The first examples of catalytic enantioselective ring-opening/cross-metathesis (EROCM) reactions that involve enol ethers are reported. Specifically, we demonstrate that catalytic EROCM of several oxa- and azabicycles, cyclobutenes and a cyclopropene with an alkyl- or aryl-substituted enol ether proceed readily in the presence of a stereogenic-at-Mo monopyrrolide-monoaryloxide. In some instances, as little as 0.15 mol % of the catalytically active alkylidene is sufficient to promote complete conversion within 10 min. The desired products are formed in up to 90% yield and >99:1 enantiomeric ratio (er) with the disubstituted enol ether generated in >90% Z selectivity. The enol ether of the enantiomerically enriched products can be easily differentiated from the terminal alkene through a number of functionalization procedures that lead to the formation of useful intermediates for chemical synthesis (e.g., efficient acid hydrolysis to afford the enantiomerically enriched carboxaldehyde). In certain cases, enantioselectivity is strongly dependent on enol ether concentration: larger equivalents of the cross partner leads to the formation of products of high enantiomeric purity (versus near racemic products with one equivalent). The length of reaction time can be critical to product enantiomeric purity; high enantioselectivity in reactions that proceed to >98% conversion in as brief a reaction time as 30 s can be nearly entirely eroded within 30 min. Mechanistic rationale that accounts for the above characteristics of the catalytic process is provided.     

Bifunctional catalyst promotes highly enantioselective bromolactonizations to generate stereogenic C-Br bonds

A novel bifunctional catalyst derived from BINOL has been developed that promotes the highly enantioselective bromolactonizations of a number of structurally distinct unsaturated acids. Like some known catalysts, this catalyst promotes highly enantioselective bromolactonizations of 4- and 5-aryl-4-pentenoic acids, but it also catalyzes the highly enantioselective bromolactonizations of 5-alkyl-4(Z)-pentenoic acids. These reactions represent the first catalytic bromolactonizations of alkyl-substituted olefinic acids that proceed via 5-exo mode cyclizations to give lactones in which new carbon-bromine bonds are formed at a stereogenic center with high enantioselectivity. We also disclose the first catalytic desymmetrization of a prochiral dienoic acid by enantioselective bromolactonization.     

Aza-Morita-Baylis-Hillman-type reactions: highly enantioselective organocatalytic addition of unmodified α,β-unsaturated aldehydes to N-Boc protected imines

Highly enantioselective catalytic routes to Boc protected aza-Morita-Baylis-Hillman-type products are presented. The organocatalytic asymmetric reactions between unmodified α,β-unsaturated aldehydes and N-Boc protected aryl imines proceed with excellent chemo- and enantioselectivity to give the corresponding compounds in good yields with 97-99% ee.     

Enantioselective intramolecular cyclopropanation of α-diazo-β-keto sulfones: asymmetric synthesis of bicyclo[4.1.0]heptanes and tricyclo[4.4.0.0]decenes

Catalytic asymmetric synthesis of some new chiral building blocks useful for natural product synthesis is described. The intramolecular cyclopropanation (IMCP) reaction of α-diazo-β-keto sulfones affording bicyclo[4.1.0]heptanes such as 9a-d is found to proceed with high enantioselectivity (93-98% ee). The yield is moderate due to the competing intramolecular C-H insertion reaction. As intramolecular C-H insertion reaction is not observed in the reaction of the substrates possessing a quaternary carbon at the allylic position, the reactions of 19a and 19b proceed with high enantioselectivity (95% ee) and yield. It was also found that the substrates possessing an ether group, such as 19a and 19b, could be used in this enantioselective IMCP reaction.     

A chiral Ag-based catalyst for practical, efficient, and highly enantioselective additions of enolsilanes to alpha-ketoesters

A Ag-based chiral catalyst promotes efficient and highly enantioselective aldol additions of ketone-derived enolsilanes to alpha-ketoesters in the presence of a readily available amino acid-based ligand and commercially available AgF2. alpha-Ketoester substrates may bear alkyl, alkenyl, and aryl substituents; reactions proceed to >98% conversion to afford the desired tertiary alcohols in 61->98% isolated yield and 60-96% ee. In contrast to previously reported approaches, highest enantioselectivities are observed with sterically demanding substrates, and reactions can be carried out in undistilled solvent, in air with as little as 1 mol % catalyst.     

A highly enantioselective Diels-Alder reaction of 1,2-dihydropyridine using a simple β-amino alcohol organocatalyst for a practical synthetic methodology of oseltamivir intermediate

An easily prepared chiral amino alcohol catalyst was found to provide an efficient synthetic intermediate of oseltamivir with excellent chemical yield and enantioselectivity (up to 98% yield and up to 98% ee) in enantioselective Diels-Alder reactions of 1,2-dihydropylidines with acroleins.     

Enantioselective Pd(II)-catalyzed aerobic oxidative amidation of alkenes and insights into the role of electronic asymmetry in pyridine-oxazoline ligands

Enantioselective intramolecular oxidative amidation of alkenes has been achieved using a (pyrox)Pd(II)(TFA)(2) catalyst (pyrox = pyridine-oxazoline, TFA = trifluoroacetate) and O(2) as the sole stoichiometric oxidant. The reactions proceed at room temperature in good-to-excellent yields (58-98%) and with high enantioselectivity (ee = 92-98%). Catalyst-controlled stereoselective cyclization reactions are demonstrated for a number of chiral substrates. DFT calculations suggest that the electronic asymmetry of the pyrox ligand synergizes with steric asymmetry to control the stereochemical outcome of the key amidopalladation step.     

Phosphine‐mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates

Phosphine‐catalyzed enantioselective annulation reactions involving ketimines are a daunting synthetic challenge owing to the intrinsic low reactivity of ketimine substrates. A highly enantioselective [3+2] cycloaddition reaction that makes use of isatin‐derived ketimines as reaction partners was developed. Notably, both simple and γ‐substituted allenoates could be utilized, and various 3,2′‐pyrrolidinyl spirooxindoles with a tetrasubstituted stereocenter were obtained in excellent yields and with nearly perfect enantioselectivity (>98 % ee in all cases).     

Enantioselective synthesis of cyclic enol ethers and all-carbon quaternary stereogenic centers through catalytic asymmetric ring-closing metathesis

The first examples of catalytic asymmetric ring-closing metathesis (ARCM) reactions of enol ethers are reported. To identify the most effective catalysts, various chiral Mo- and Ru-based catalysts were screened. Although chiral Ru catalysts (those that do not bear a phosphine ligand) promote ARCM in some cases, such transformations proceed in <10% ee. In contrast, Mo-based alkylidenes give rise to efficient ARCM and deliver the desired products in the optically enriched form. Thus, Mo-catalyzed enantioselective transformations allow access to various five- and six-membered cyclic enol ethers in up to 94% ee from readily available achiral starting materials. The first examples of catalytic ARCM that lead to the formation of all-carbon quaternary stereogenic centers are also disclosed. Mechanistic models that offer a plausible rationale for the identity of major enantiomers as well as the observed levels of enantioselectivity are provided. Representative examples demonstrate that the enol ether moiety and the unreacted alkene of the ARCM products can be discriminated with excellent site selectivity (>98%).     

高对映选择性有机催化的七元环状亚胺二苯并1,4-氧氮杂卓和丙酮的直接Mannich反应(英文)

用脯氨酸作为催化剂,研究了各种取代的二苯并1,4-氧氮杂卓衍生物类七元环状亚胺和丙酮的直接Mannich反应,该反应能高对映选择得到一系列旋光活性的含有β羰基的七元环状氮杂环化合物(93%–98%ee).用丁酮作为Mannich给体时,能得到专一的区域选择性和96%–97%ee的产物.进一步通过X射线单晶衍射分析其中一个产物的衍生物,确定了产物手性中心绝对构型为R,其它同类型产物绝对构型随后通过化学类比方法推断确认.     

Enhancement of enantioselectivity by THF in asymmetric mo-catalyzed olefin metathesis. Catalytic enantioselective synthesis of cyclic tertiary ethers and spirocycles

Mo-catalyzed enantioselective rearrangement of achiral cyclopentenyl tertiary ethers to chiral cyclohexenyl tertiary ethers are reported. These olefin metathesis transformations proceed efficiently and with high levels of enantioselectivity. A noteworthy feature of these reactions is that added tetrahydrofuran exerts a remarkably positive influence on the enantioselectivity of the metathesis-based rearrangement. The first examples of catalytic asymmetric synthesis of spirocyclic structures by enantioselective olefin metathesis are also disclosed.     

Broadly Applicable Z‐ and Diastereoselective Ring‐Opening/Cross‐Metathesis Catalyzed by a Dithiolate Ru Complex

A broadly applicable Ru‐catalyzed protocol for Z‐selective ring‐opening/cross‐metathesis (ROCM) is disclosed. In addition to reactions relating to terminal alkenes of different sizes, the first examples of Z‐selective ROCM processes involving heteroaryl olefins, 1,3‐dienes, and O‐ and S‐substituted alkenes as well as allylic and homoallylic alcohols are reported. Z‐Selective transformations with an α‐substituted allylic alcohol are shown to afford congested Z alkenes with high diastereoselectivity. Transformations are performed in the presence of 2.0–5.0 mol % of a recently disclosed Ru‐based dithiolate complex that can be easily prepared in a single step from commercially available starting materials. Typically, transformations proceed at ambient temperature and are complete within eight hours; products are obtained in up to 97 % yield, >98:2 Z/E, and >98:2 diastereomeric ratio. The present investigations reveal a mechanistically significant attribute of the Ru‐based dithiolates that arises from electrostatic interactions with anionic S‐based ligands.     

Enantioselective addition of allyltin reagents to amino aldehydes catalyzed with bis(oxazolinyl)phenylrhodium(III) aqua complexes

Bis(oxazolinyl)phenylrhodium(III) aqua complexes, (Phebox)RhX?(H?O) [X = Cl, Br], were found to be efficient Lewis acid catalysts for the enantioselective addition of allyl- and methallyltributyltin reagents to amino aldehydes. The reactions proceed smoothly in the presence of 5-10 mol % of (Phebox)RhX?(H?O) complex at ambient temperature to give the corresponding amino alcohols with modest to good enantioselectivity (up to 94% ee).     

A practical method for enantioselective synthesis of all-carbon quaternary stereogenic centers through NHC-Cu-catalyzed conjugate additions of alkyl- and arylzinc reagents to beta-substituted cyclic enones

We present the first examples of Cu-catalyzed enantioselective conjugate additions of alkyl- and arylzinc reagents to unactivated cyclic beta-substituted enones. Transformations are promoted in the presence of 2.5-15 mol % of a readily available chiral NHC-based Cu complex, affording the desired products bearing all-carbon quaternary stereogenic centers in 67-->98% yield and in up to 97% ee. Catalytic enantioselective reactions can be carried out on a benchtop, with undistilled solvent and commercially available (not further purified) Cu salts. Mechanistic models, accounting for the observed levels and trends in enantioselectivity are provided.     

Asymmetric catalytic Mannich reactions catalyzed by urea derivatives: enantioselective synthesis of beta-aryl-beta-amino acids

Highly enantioselective addition reactions between silyl ketene acetals and N-Boc aldimines are catalyzed by the thiourea-based catalyst 1c. Extraordinary scope is observed in this methodology with regard to the imine substrate, with aryl and heteroaromatic derivatives generally affording nearly quantitative yields of beta-amino ester product in up to 98% enantioselectivity.     

New catalysts for the base-promoted isomerization of epoxides to allylic alcohols. Broadened scope and near-perfect asymmetric induction

Optically active (1S,3R,4R)-3-[N-(trans-2,5-dialkyl)pyrrolidinyl]methyl-2-azabicyclo-[2.2.1]heptanes were evaluated as catalysts for the enantioselective beta-elimination of meso-epoxides. The (2R,5R)-dimethylpyrrolidinyl-substituted catalyst 4 exhibited exceptionally high enantioselectivity and reactivity, and several substrates were rearranged with enantioselectivities of 98-99% ee. In addition, the use of 4 allowed the first successful, true catalytic rearrangement of the difficult substrates cyclopentene oxide (81%, 96% ee) and (Z)-4-octene oxide (80%, 91% ee).     

Asymmetric intermolecular C-H functionalization of benzyl silyl ethers mediated by chiral auxiliary-based aryldiazoacetates and chiral dirhodium catalysts

[reaction: see text] C-H functionalization of benzyl silyl ethers by means of rhodium-catalyzed insertions of aryldiazoacetates can be achieved in a highly diastereoselective and enantioselective manner by judicious choice of chiral catalyst or auxiliary. The dirhodium tetraprolinates such as Rh2((S)-DOSP)4 have been widely successful as chiral catalysts in the C-H functionalization chemistry of aryldiazoacetates, but give poor enantioselectivity in the reactions of aryldiazoacetates with benzyl silyl ether derivatives. The use of (S)-lactate as a chiral auxiliary resulted in C-H functionalization with moderately high diastereoselectivity (79-88% de) and enantioselectivity (68-85% ee). The best results (91-95% de, 95-98% ee), however, were achieved using Hashimoto's Rh2((S)-PTTL)4 catalyst.     

Enantioselective N‐Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut–Currier Reaction

While the enantioselective Rauhut–Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high‐nucleophilicity N‐heterocyclic carbenes, it is possible to achieve Rauhut–Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

Palladium-catalyzed asymmetric arylation,vinylation, and allenylation of tert-cyclobutanols via enantioselective C-C bond cleavage

A novel enantioselective C-C bond cleavage has been achieved using palladium catalysts and chiral N,P-bidentate ligands in the asymmetric arylation, vinylation, and allenylation of tert-cyclobutanols. In these reactions, the enantioselective beta-carbon elimination of Pd(II) alcoholate formed in situ is the key step. Treatment of tert-cyclobutanols with arylating reagents in toluene in the presence of Pd(OAc)(2), a chiral ferrocene-containing N,P-bidentate ligand, and Cs(2)CO(3) affords optically active gamma-arylated ketones in excellent yields with high enantioselectivity (up to 95% ee). When vinylating reagents are used in place of arylating ones, the asymmetric vinylation also proceeds to afford optically active gamma-vinylated ketones in high yields with good to high enantioselectivity. When propargylic acetates are used, which are known to generate (sigma-allenyl)palladium complexes with Pd(0) species, asymmetric allenylation occurs to afford optically active gamma-allenylated ketones in moderate to good yields with moderate to high enantioselectivity.